A range of different approaches have been used for modifying the structure of GLP-1 compounds in order to provide a longer duration of action in vivo.
WO 2006/097535 discloses various peptide agonists of the glucagon family with secretin like activity and their therapeutic use. GLP-1(7-37) derivatives comprising a modified GLP-1(7-37) sequence are disclosed in Examples 3 and 5 thereof. These derivatives, however, do not have a Glu residue at position 22 and an Arg residue at position 26.
WO 01/04156 discloses peptides that lower blood glucose levels. Compounds 4, 5, 6, 7, 10, 11, 12, and 13 thereof are GLP-1 derivatives, however none of these compounds have a Glu residue at position 22 and an Arg residue at position 26.
EP 1364967 discloses glucagon-like insulinotropic peptides, compositions and methods. None of the five GLP-1 compositions of Example 1 thereof comprises a modified GLP-1 sequence having Glu at position 22 and Arg at position 26.
WO 98/08871 discloses protracted GLP-1 derivatives including liraglutide, which is a GLP-1 derivative for once daily administration developed by Novo Nordisk A/S. Liraglutide is expected to be marketed for the treatment of type 2 diabetes as of 2009. Liraglutide does not have Glu at position 22 and Arg at position 26. The derivative disclosed in Example 30 of this reference does, but is not derivatised in position 18, 20, 23, 30, 31, 34, 36, 37, or 39.
WO 2005/027978 discloses novel GLP-1 derivatives including three which comprise a modified GLP-1(7-37) sequence having a Glu at position 22 and an Arg at position 26. These derivatives, however, are not derivatised in position 18, 20, 23, 30, 31, 34, 36, 37, or 39.
Runge et al (Journal of Biological Chemistry, vol. 283, no. 17, pp. 11340-11347), which was published after the priority dates of the present invention, discloses the crystal structure of the extracellular domain of the ligand-bound GLP-1 receptor.
Many diabetes patients particularly in the type 2 diabetes segment are subject to so-called “needle-phobia”, i.e. a substantial fear of injecting themselves. In the type 2 diabetes segment most patients are treated with oral hypoglycaemic agents, and since GLP-1 compounds are expected to be an injectable pharmaceutical product these patients will be administered, the fear of injections may become a serious obstacle for the widespread use of the clinically very promising compounds. Thus, there is a need to develop new compounds which can be administered less than once daily, e.g. once every second or third day preferably once weekly, while retaining an acceptable clinical profile or optionally via non invasive administration such as pulmonary, nasal, sublingual, bucal or oral administration.
One object of the present invention is to provide a chemically, physically and enzymatically stable GLP-1 derivative, preferably with a high alpha-helical content.
A further object of the invention is to provide a long acting, i.e. having an administration regimen as described above, GLP-1 derivative.
Another object of this invention is to provide a GLP-1 derivative with high potency (receptor affinity) in order to reduce the therapeutic dose used for example for once weekly s.c. dosing or alternatively for non-invasive delivery.
Another object of this invention is to provide a GLP-1 derivative with a high binding affinity to the extracellular domain of the GLP-1 receptor (GLP-1R).
Another object of this invention is to provide a GLP-1 derivative with high albumin binding affinity which protects the peptide for proteolytic degradation and reduce renal clearance of the peptide.
Potency, stability, half-life, binding affinity to albumin, and binding affinity to the extracellular domain of the GLP-1 receptor are properties of potential relevance for an overall object of achieving long-acting, stable and of course therapeutically active GLP-1 derivatives with a potential for once weekly administration.